Thach Tuan Pham, Anh Hong Le, Cong Phi Dang, Suet Yen Chong, Dang Vinh Do, Boya Peng,
Migara Kavishka Jayasinghe, Hong Boon Ong, Dong Van Hoang, Roma Anne Louise, Yuin-Han Loh,
HanWei Hou, Jiong-WeiWang, Minh TN Le
Abstract
Extracellular vesicles (EVs) can be produced from red blood cells (RBCs) on a large
scale and used to deliver therapeutic payloads efficiently. However, not much is
known about the native biological properties of RBCEVs. Here, we demonstrate that
RBCEVs are primarily taken up by macrophages and monocytes. This uptake is an
active process, mediated mainly by endocytosis. Incubation of CD14+ monocytes
with RBCEVs induces their differentiation into macrophages with an Mheme-like
phenotype, characterized by upregulation of heme oxygenase-1 (HO-1) and the ATPbinding
cassette transporter ABCG1. Moreover, macrophages that take up RBCEVs
exhibit a reduction in surface CD86 and decreased secretion of TNF-α under inflammatory
stimulation. The upregulation of HO-1 is attributed to heme derived from
haemoglobin in RBCEVs. Heme is released from internalized RBCEVs in late endosomes
and lysosomes via the heme transporter, HRG1. Consequently, RBCEVs
exhibit the ability to attenuate foamcell formation fromoxidized low-density lipoproteins
(oxLDL)-treated macrophages in vitro and reduce atherosclerotic lesions in
ApoE knockout mice on a high-fat diet. In summary, our study reveals the uptake
mechanism of RBCEVs and their delivery of heme to macrophages, suggesting the
potential application of RBCEVs in the treatment of atherosclerosis.